N-tertiary-4-aminomethyl-dibenzo(b,e)-11-oxepine-2&#39;-spiro-1&#39;,3&#39;-dioxolanes

ABSTRACT

1. A COMPOUND OF THE FORMULA   2-Z,11-(4-(R-N(-R&#39;&#39;)-CH2-)-1,3-DIOXOLAN-2,2-YLIDENE&lt;)-   DIBENZ(B,E)OXEPIN   IN WHICH Z IS HYDROGEN ALKOXY HAVING 1 TO 4 CARBON ATOMS, OR HALOGEN, AND R AND R&#39;&#39; EACH IS ALKYL HAVING 1 TO 3 CARBON ATOMS, OR   -N(-R&#39;&#39;)-R   IS PYRROLIDINO, PIPERIDINO, MORPHOLINO, HEXAMETHYLENEIMINO, PIPERAZINO, OR PIPERAINE SUBSTITUTED AT N&#39;&#39; BY ALKYL HAVING 1 TO 3 CARBON ATOMS, HYDROXYALKYL HAVING 1 TO 3 CARBON ATOMS AND ONE OR TWO HYDROXYL, AMINOCARBONYLMETHYL, AMINOCARBONYLMETHYL SUVSTITUTED AT N BY ONE OR TWO ALKYL HAVING 1 TO 3 CARBON ATOMS, PYRROLIDINO, MOR PHOLINO OR HEXAMETHYLENEIMINO, AND THE PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.

United States Patent Ofioe- Patented Oct. 29, 1974 3,845,046 N-TERTIARY-4-AMlNOMETHYLDIBENZO(b,e)-11- XEPlNE-2'-SPIRO-1',3'-DIOXOLANES Claude P. Fauran and Guy M. Raynaud, Paris, Jeannine A. Eberle, Chatou, Bernard M. Pourrias, Meutlon-la- Foret, and Albert Y. Le Cloarec, Saint-Maur, France, assignors to Delalande S.A., Henri-Regnault, France No Drawing. Filed May 25, 1972, Ser. No. 256,655 Claims priority, application France, May 28, 1971, 7119501; Mar. 23, 1972, 7210250 Int. Cl. C07d 21/00 US. Cl. 260-247.5 R 9 Claims ABSTRACT OF THE DISCLOSURE A compound of the formula ZUV A CH2N wherein Z is hydrogen, alkoxy having from 1 to 4 carbon atoms, or halogen; and R and R each represent alkyl having from 1 to 3 carbon atoms, or

is pyrrolidine, piperidino, morpholino, hexamethyleneimino or piperazino, the piperazino radical being N'- substituted with alkyl having 1 to 3 carbon atoms which alkyl is optionally substituted with one or two hydroxyl groups, or by an aminocarbonylmethyl radical the nitro' gen atom of which is optionally substituted by one or two alkyls having 1 to 3 carbon atoms or belongs to a pyrroldino, morpholino, or hexamethyleneimino group. The compounds possess analgesic, respiratory analeptic, bronchodilatory, antitussive, anti-inflammatory, spasmolytic, vasodilatatory, hypotensive, antithistaminic, atropinic, neuroleptic, tranquilizing, sedative, diuretic and capillary permeability modifying properties.

The present invention relates to novel compounds, which are N-tertiary-4 aminomethyl-dibenzo[b,e]-l1- oxepine-2'-spiro-l',3'-dioxolanes.

The compounds correspond to the formula:

in which: a

Z represents a hydrogen atom, an alkoxy radical having from 1 to 4 carbon atoms, or a halogen atom; and

R and R each represent an alkyl radical having from 1 to 3 carbon atoms, or R and R together with the nitrogen atom to which they are attached, form a pyrrolidino, piperdino, morpholino, a hexamethylene-imino or a piperazine radical, said piperazino radical being N'-substituted by an alkyl radical having 1 to 3 carbon atoms optionally substituted by one or two hydroxy groups or by an aminocarbonylmethyl radical the nitrogen atom of which is optionally substituted by one or two alkyl radicals having 1 to 3 carbon atoms or belongs to an heterocyclic radical selected from: pyrrolidino, morpholino, hexamethyleneimino.

The process according to the invention comprises, in a first stage, reacting 6H-dibenzo[b,e]-oxepine-1l-one, optionally substituted in the 2-position, and corresponding to the formula:

ii (II) in which Z has the same signification as in formula I), with epibromohydrin of formula:

CH1-CHCH Br (III) in the presence of tin tetrachloride, and then in a second stage, reacting the 4-bromomethyl dibenzo[b,e]-1loxepine-2-spiro-l,3-dioxolane, optionally substituted in the 2-position, thereby obtained of formula:

i CH Br (IV) with an amine of formula:

/R HN\ in which R and R have the same significance as in formula (I).

The following preparation is described by way of example to illustrate the invention.

EXAMPLE 4-pyrrolidinomerhyl-dibenzo[b,e]-11-0xepine-2'-spiro 1',3'-di0xolane muleate (Code No. 7135) 1ST. STAGE 2ND STAGE Preparation of 4'-pyrrolidin0methyl-gjibenzo[b,e]-11- oxepine-2'-spira-1',3'-dioxolane. 33 g. of the compound prepared in the 1st stage is mixed with 31 g. of pyrrolidine in ml. of benzene. The solution is maintained under benzene reflux for -8 hours. An equivalent of soda is then added, and the product is washed with water, dried, evaporated and distilled.

The resultant compound is obtained in a yield of 82.5

Boiling point=2l0 C. under 0.1 mm. Hg.

3RD STAGE v I Preparation of 4-pyrroli iinomethyl-dibenzo[b,e]-11- oxepine-Z'-spir0-I',3'-di0x0lane maleate. The base obtained is converted to the maleate by the addition of an equivalent of maleic acid. The product obtained is recrystallised in 96 aIcohol.'-'-" Y Melting point=168'C.

' TABLE I.

Yield=81%.

Empirical formula=Cg H NO Elementary analysis: Calculated (percent): C, 66.21; H, 6.00; N, 3.09. Found (percent): C, 66.35; H, 5.96; N, 3.27.

The compounds listedfin' the following Tables I, II and- III ave been prepared by the same methods of 91 941 9 5 R Elementary analysis Boiling N Molecoint Melting Calculated Found Empirical ular 0. mm. point Yield Code No. R Form formula weight Hg) C (percent) 0 H N C H N 7180 ..-N(CH3)4 04411413107- 427.44 164 84 64.62 5.90 3.23 64.67 5.97 3.41 7155 N(CH) 7, 3486..- C4|H25N01 339.42 1805/0.05 63 74.31 7.42 413 74.13 7.29 4.24 Oxalate C44H4'1N O1 429.45--.......-.- 139 48 64.32 0.34 3.26 64.42 6.27 3.45 7135 M5i9 te.-.-. 04111411601 163 31 66.21 6.00 3.09 66.35 5.96 3.27

7131 /fi :.;-.d0 04411451601 467.50 118, 36 6.79 6.25 3.00 66.59 6.36 3.16

7156 .-..-do C25H21N0| 469.48 166 91 63.95 5.30 2.93 64.15 5.60 3.13

71107--.-1... Hydrochloride.. CzaHzaOlNO: 401.92 199 41 68.73 7.02 3.49 68.83 7.02 3.63

TABLEAU 1 (SUITE) v.Ofo R ---CH3-N dlmaleate \R. v

/R Elementary analysis --N Molec- Melting Calculated Found Empirical u1a r, Yield point; 0066 NO. R formula weight 1666 4 0.) o H N o H N 72133 CzuHaaNzOu 598.53 "50 178 60.19 5.73 468 59.93 5.34 4.34

- -N -NCH| p I 1 1 72215 .CnHanNaOxa 658.64 18 148 58.35 5.32 4.25 58.23 6.04 4.45 N N-CHz-CHOH-CHzOH v 72112 061141164014. 655.64 39 128 (1) N N-CHr-CO-NHGHr 72135 cm 0441511164011 633.69 51 162 59.73 6.04 6.15 59.56 6.17 .34

-16 'N -oH4-'c0NH-o'n r CH8 4 7262...:.:;..: cm CaaHnNzOn 669.66 61 176 59.13 5.37 6.23 59.19 5.91 6.08

N /N-OH2-C0N I I H CH3 7245 B11116) v011116161014 725.77 51 152 01.22 6.53 5.79 61.02 6.38 5.87

-N N-QHz-GON\ 0437(0) 71576..:.-.: 'Ca5H|1Na0l3 695.70 .63 174 60.42 5.94 6.04 60.22 5.98 5.35

N N-OHz-CO-N I 1 TABLE I-Continued /R Elementary analysis N Molec- Melting Calculated Found Empirical ular Yield point Code No. R formula weight (percent) C.) C H N C H N 7205 CSsHuNsOx: 711.70 50 175 59.06 5.81 5.90 58.85 5.99 6.07

N NCH:-CON E) 72141 CavHwNzOn 723.75 38 172 61.40 6.27 5.81 61.26 6.42 5.97

-N N-CHz-CON 7284 CuHuNaOn 683.69 56 160 59.73 6.04 6.15 59.54 6.22 6.2

N N-CHz-CONHCaHKn) 1 Protometryn-Acid. calculated: 35.4; Acld. found: 34.6; Base, calculated: 64.6; Base, found: 63.2; Water (Karl Fischer) 1.45.

TABLE II /R CH N /R Elementary analysis -N Molec- Melting Calculated Found Emplrlcal ular point Code No. R Form formula weight C.) C H N C H N 71400 /CH: Oxalate- CmHzaNOa 341.39 74 70.36 6.79 4.10 70.18 6.67 4.29

CHI

71309 13850.... C2zH2sN04 367.42 90-91 71.91 6.86 3.81 71.72 6.77 3.93

71518 N/ \0 Oxalate. C24H21N0 473.46 196 60.88 5.75 2.96 60.91 5.89 3.13

71454.... D -..-do-.. CzaHaxNOa 485.51 155 64.32 6.44 2.89 64.12 6.51 3.06

I Decomposition.

TABLE III /0\ Q /R CHr-N oxalate /R Elementary analysis -N Molec- Melting Calculated Found Empirlcal ular point Code No. R formula weight 0 C.) Yield 0 H N C H N 71365 N/CH: C2|H22C1NO1 435.85 216 70 57.87 5.09 3.21 57.98 4.90 3.19

71367....;...; C2H| CzsHzuClNO: 463.90 176 59 59.54 5.65 3.02 59.58 5.82 2.95

L 71360 N: CMHaClNOI 475.91 247 39 60.57 5.51 2.94 60.42 5.49 2.93

71396 CzaHzgClNO: 489.93 196 50 71.28 5.76 2.86 61.44 5.94 2.75

l Decomposition.

The compounds of formula (I) have been studied on animals in the laboratory and have been shown to possess analgesic, respiratory analeptic, bronchodilatatory antitussive, anti-inflammatory, spasmolytic, Vasodilatatory, hypotensive, antihistaminic, atropinic, neuroleptic, tranquillising, sedative, diuretic and capillary permeability modificational properties.

1. Analgesic properties The compounds of'formula (I), administered by oral means to mice, are capable of reducing 'the number of painful stretchings produced by the intraperitoneal injection of acetic acid or phenyl benzoquinone.

The results obtained with a certain number of compounds are given in the following Table IV.

TABLE IV Dose Percentage protection administered against an c/ Code No. of Phenyl Acetic compound tested benzoquinone acid 2. Respiratory analeptic properties The compounds of formula (1), administered by intraveinous means to an anaesthetised guinea pig, are capable of opposing the respiratory depression provoked by morphine.

The results obtained with three of the compounds, administered in a dose of 2.5 mg./kg./IV are given in the following Table V:

TABLE V Increase in respiratory frequency Intensity Duratio Code N o. 0! compound tested (percent) (mn.)

3. Antitussive properties The compounds of formula (I), administered by intraveinous and intraduodenal means reduce the coughing provoked by stimulation of the upper laryngeal nerve in the anaesthetised cat.

By Way of examples, the results obtained with a certain number of the compounds are given in the following Table VI:

TABLE VI Reduction of coughing Code No. of Dose Intensity compound tested administered (percent) Duration 7135 mgJkgJID--- 75 45 run. 7155. 1 mg./kg./ 70 11m. 7156... 1 mg./kg./I 80 Inn. 7180... mg./kg. 60 60 Inn. 7181 1 mg.lkg./IV... 60 3 h. 71107 500 gJkgJl'V--. 40 mu.

4. Bronchodilatatory properties The compounds of formula (I), injected by intraveinous means, are capable of opposing the bronchoconstriction provoked in the guinea pig by the intraveinous injection of acetylcholine and evaluated according to the Konzett method.

Also, in adose of 500 pg./kg./IV, the compound No. 7180 inhibits the bronchoconstriction by 5. Anti-inflammatory properties These properties are shown by a diminution of the underplanatary oedema provoked by the local injection of a phlogogenic agent, such as carraghenine, to a rat following oral administration of the compounds of formula (I).

The results obtained with certain of the compounds are given in the following Table VII:

TABLE VII Percentage Dose diminution administered of the Code N o. of compound tested, (rngJkgJPO) oedema 6. Spasmolytic properties TABLE VIII Spasmolytic Code No. of compound tested activity 7135. 2.5x papaverlne. 7155 10X papaverine. 7180- 14X papaverine. 7181- 1.5x papaverine. 71107. 5X papaverine.

7. Vasodilatatory properties The compounds of formula (I) are capable of augment ing the flow of the coronary vessels of the isolated heart of a guinea-pig when said compounds are added in the perfusion liquid of said organ.

The compounds Nos. 7155, 7156 and 7180 in a dose of 2.5 ,ugJml. in the perfusion liquid, augment the flow of coronary vessels by 85, 40 and respectively.

8. Hypotensive properties Administered by intraveinous means to an anaesthetised rat, the compounds of formula (I) provoke a lowering of the arterial pressure.

The results obtained with a certain number of compounds are given in the following Table IX:

TABLE IX Reduction of arterial pressure Dose Code No. of administered Intensity Duration compound tested (mg./kg./IV) (percent) (mn.)

9. Antihi'staminic properties The compounds of formula (I) introduced in the conserving medium are capable of opposing the contractural action of histamine hydrochloride on the isolated ileum of a guinea-pig.

The DE 50 of several of the compounds are given in the following Table X:

TABLE x DE 50 anti- Code No. of histaminic,

compounds tested ug/ml.

This activity is evaluated by taking mepyramine as standard.

The results obtained with several compounds of formula (I), expressed in this manner, are given in the following Table XI:

TABLE XI Code No. of Antihisteminic compound tested activity 7135. 1/5)( mepy'ramine. 7155. 1/20X mepyramine. 7180- 1/5X mepyramine. 7181. 1/15X mepyrannne.

10. Atropinic properties The compounds of formula (I), introduced in the conserving medium are capable of opposing the contractural action of acetylcholine on the isolated duodenum of a rat.

By way of examples, the DE 50 of compounds Nos. 71365 and 71367 is 1.25 ,ug./ml. and 0.75 pg./ml., respectively.

11. Neuroleptic properties The compounds of formula (I), administered by oral means, are capable of provoking catalepsy in the mouse.

The administration of 50 mg./kg./PO of compound No. 71365 provoke catalepsy in 50% of mice treated.

12. Tranquillising properties Administered by oral means, the compounds of formula (I) are capable of inhibiting the aggressiveness provoked in the mouse by electric stimulation.

This inhibition is attained by administration of 25 mg./kg./PO of compound No. 71365.

13. Sedative properties The compounds of formula (I), administered by oral means to the mouse, reduce the number of explorations in an escape enclosure and in actimetry with a pencil of rays and with photoelectric cells and induce narcosis when treated with an infrahypnotic dose of penthiobarbital (30 mg./kg./i.p.).

The results obtained with a certain number of the compounds according to the invention are given in the following Table XII.

14. Diuretic properties The compounds of formula (I), administered by oral means to the mouse simultaneously with a volume of 1 m1. of an isotonic solution of sodium chloride per 25 g. of the corporeal weight of the mouse, are capable of provoking an augmentation of the volume of urine emitted by reference to control animals, the volume being measured for 4 hours following administration.

This augmentation is 50% following the administration of 20 mg./kg./PO of compound No. 71365 or 71396.

15. Capillary permeability modificational properties The compounds of formula (I), administered by oral means to the guinea-pig, are capable of reducing the augmentation of the capillary permeability provoked by the intradermic injection of histamine and evaluated by the diffusion at the level of the papula so formed by a colorant, such as Evans blue or Trypan blue, injected by general means.

By way of example, the compound No. 7135 reduced the capillary permeability by 50% in a dose of 70 mg./ kg./PO.

As can be seen from the results expressed above and those shown in the following Table XII-I, the difierence between the pharmacologically active dose and the lethal dose is sufficiently great to permit the compounds of formula (I) to be used in therapeutics.

TABLE XIII Dose administered Percentage Code No. of compound tested (mgJkgJPO) mortality The compounds of formula (I) are useful in the treatment of diverse originating pains, respiratory insufiiciencies, coughs, asthma, allergies, oedemas, visceral and vasculary spasms, hypertension, circulatory insufiiciencies, gastric hypersecretion, anxiety, neurosis, psychosis, depressions and capillary permeability troubles.

They may be administered by oral means in the form of tablets, dragees and gelules containing 25 to 400 mg. of active ingredient (l to 5 times a day), in the form of drinkable liquids in doses of 0.1 to 2% (30 to drops, 3 times a day) or in the form of a syrup in a dose of 0.1 to 2% (2 to 6 spoonfuls per day), by parenteral means in the form of injectable ampoules containing 1 to mg. of active ingredient (1 or 2 times a day) and by rectal means in the form of suppositories containing 25 to 400 mg. of active ingredient (1 or 2 times a day).

Accordingly, the present invention relates to a compound of the general formula (I). This compound can be mixed together with a therapeutically-acceptable carrier to form a therapeutic composition.

What we claim is:

1. A compound of the formula I CHr-N in which Z is hydrogen, alkoxy having 1 to 4 carbon atoms, or halogen, and R and R each is alkyl having 1 to 3 carbon atoms, or

methyl, aminocarbonylmethyl substituted at N by one or two alkyl having 1 to 3 carbon atoms, pyrrolidino, morpholino or hexamethyleneimino, and the pharmacologically acceptable acid addition salts thereof.

2. A compound according to Claim 1, in which Z is hydrogen and R and R each is methyl.

3. A compound according to Claim 1, in which Z is hydrogen and R and R each is alkyl having 1 t0 3 carbon atoms.

4. A compound according to Claim 1, in which R and R each is alkyl having 1 to 3 carbon atoms.

5. A compound as claimed in Claim 1, in which Z is hydrogen.

is pyrrolidino, piperidino, morpholino or hexamethyleneimino.

9. A compound as claimed in Claim 1, in which is piperazino or piperazino substituted at N by alkyl hav ing 1 to 3 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms and one or two hydroxyl, aminocarbonylmethyl, aminocarbonylmethyl substituted at N by one or two alkyl having 1 to 3 carbon atoms, pyrrolidino, morpholino or hexamethyleneimino.

References Cited UNITED STATES PATENTS 3,652,558 3/1972 Lunsford et a1. 260-268 TR 3,718,665 2/1973 Yale 260326.81 3,726,900 4/1973 Fauran et a1. 260340.9 3,763,169 10/1973 Malen et al 260293.58

RICHARD GALLAGHER, Primary Examiner US. Cl. X.R.

260-247.7 A, 247.7 F, 268 TR, 293.58, 326.81, 340.9; 424-248, 251, 267, 274, 278

Attesting Officer UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3 845 046 Dated October-'29. 1974 Claude P. Fauran, Guy M. Raynaud, Jeannine A. Eberle, Invento Bernard M. Pourrias and Albert Y. Le Cloarec Patent No.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 10, lines 55-63; please change the formula to read as follows Signed and sealed this 14th day of January 1975.

(SEAL) Attest:

MCCOY M. GIBSON JR. C. MARSHALL DANN Commissioner of Patents F ORM PO-1050 (1 O69) USCOMM-DC 60376-P69 u,s GOVERNMENT PRINTING orncz; 930 

1. A COMPOUND OF THE FORMULA 